Biology subjects

Standal, T.

Publications and source records attributed to Standal, T..

5 recordsLinked to original sources

bioRxiv2025

Highly multiplexed imaging recovers immune and metabolic niches in multiple myeloma associated with disease progression and bone involvement

Multiple myeloma (MM) is a cancer arising from genetically aberrant plasma cells (PCs) that remain dependent on the bone marrow (BM) microenvironment for disease establishment and progression. Here, we spatially mapped BM biopsies from patients with MM, smoldering MM and monoclonal gammopathy of undetermined significance by imaging mass cytometry. We found that PCs near bone surfaces were quiescent and demonstrated a distance-to-bone-dependent upregulation of IL-32 and HIF1 in patients with bone disease, consistent with their role in promoting bone loss in MM. We further identified two distinct PC neighborhoods termed PC_OXPHOS characterized by focal PC growth, enrichment of endothelial cells and elevated oxidative phosphorylation; and PC_MYELOID, characterized by PCs interspersed with immune cells and featuring a glycolytic phenotype. Spatial interactions between PCs and immune correlated with shorter progression free survival. Notably, a strong neighbor preference between PCs and CD4+ T cells was an independent predictor for disease progression. Our work underscores spatial context as a key factor in understanding MM pathogenesis and the potential for spatial analyses to improve MM risk stratification. SignificanceThis study demonstrates that MM cells in different neighborhoods experience unique metabolic conditions and immune environments, and that neighbor preference of CD4+ T cells and plasma cell is associated with disease progression. These features were not captured by non-spatial metrics, highlighting the value of spatially resolved analyses in uncovering pathophysiological mechanisms of MM.

cancer biology↗

bioRxiv2025

Novel SLAMF1-derived peptide induces apoptosis in multiple myeloma cells by targeting IRF4 transcription factor for degradation

Multiple myeloma (MM) is the second most common hematological cancer. It remains incurable, highlighting the urgent need for novel therapeutic targets and treatment strategies. In this study, we investigated a panel of peptides derived from a functional motif of Signaling Lymphocytic Activation Molecule Family 1 (SLAMF1) with single amino acid substitutions and found that several of them exhibited potent anti-cancer activity by inducing MM cell death. The most potent peptide P7N4 significantly reduced the viability of both IL-6-dependent and -independent human myeloma cell lines (HMCLs), proteasome inhibitor-resistant MM cells, and primary MM cells, while exerting minimal effects on healthy blood cells. Furthermore, P7N4 enhanced the efficacy of the chemotherapeutic agent melphalan. When combined with the proteasome inhibitor bortezomib, P7N4 potentiated the anti-cancer effect of bortezomib in a highly aggressive murine MM model. Mechanistically, P7N4 induced apoptosis in MM cells by disrupting key pro-survival pathways, leading to reduction in IRF4, MYC, and {beta}-catenin levels, as well as inhibition of Akt and ERK1/2 phosphorylation. Furthermore, in peptide-sensitive HMCL, P7N4 significantly altered the expression of IRF4-associated genes. These effects were likely mediated by direct interaction of peptide with IRF4, targeting this transcription factor for degradation. Overall, our findings established P7N4 as a promising therapeutic candidate for MM, warranting further optimization and in-depth mechanistic studies.

cancer biology↗

bioRxiv2024

Interpreting single-cell messages in normal and aberrant hematopoiesis with the Cell Marker Accordion

Single-cell technologies offer a unique opportunity to explore cellular heterogeneity in health and disease. However, reliable identification of cell types and states represents a bottleneck. Available databases and analysis tools employ dissimilar markers, leading to inconsistent annotations and poor interpretability. Furthermore, current tools focus mostly on physiological cell types, limiting their applicability to disease. We developed the Cell Marker Accordion, a user-friendly platform providing automatic annotation and unmatched biological interpretation of single-cell populations, based on consistency weighted markers. We validated our approach on multiple single-cell and spatial datasets from different human and murine tissues, improving annotation accuracy in all cases. Moreover, we show that the Cell Marker Accordion can identify disease-critical cells and pathological processes, extracting potential biomarkers in a wide variety of disease contexts. The breadth of these applications elevates the Cell Marker Accordion as a fast, flexible, faithful and standardized tool to annotate and interpret single-cell and spatial populations in studying physiology and disease.

bioinformatics↗

bioRxiv2021

IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

IL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

cancer biology↗

bioRxiv2019

Bone morphogenetic protein 4 gene therapy in mice inhibits myeloma tumor growth, but has a negative impact on bone

Multiple myeloma is characterized by accumulation of malignant plasma cells in the bone marrow. Most patients suffer from an osteolytic bone disease, caused by increased bone degradation and reduced bone formation. Bone morphogenetic protein 4 (BMP4) is important for both pre- and postnatal bone formation and induces growth arrest and apoptosis of myeloma cells. BMP4-treatment of myeloma patients could have the potential to reduce tumor growth and restore bone formation. We therefore explored BMP4 gene therapy in a human-mouse model of multiple myeloma where humanized bone scaffolds were implanted subcutaneously in RAG2-/- {gamma}C-/-mice. Mice were treated with adeno-associated virus serotype 8 BMP4 vectors (AAV8-BMP4) to express BMP4 in the liver. When mature BMP4 was detectable in the circulation, myeloma cells were injected into the scaffolds and tumor growth was examined by weekly imaging. Strikingly, the tumor burden was reduced in AAV8-BMP4 mice compared with the AAV8-CTRL mice, suggesting that increased circulating BMP4 reduced tumor growth. BMP4-treatment also prevented bone loss in the scaffolds, most likely due to reduced tumor load. To delineate the effects of BMP4 overexpression on bone per se, without direct influence from cancer cells, we examined the unaffected, non-myeloma femurs by CT. Surprisingly, the AAV8-BMP4 mice had significantly reduced trabecular bone volume, trabecular numbers, as well as significantly increased trabecular separation compared with the AAV8-CTRL mice. There was no difference in cortical bone parameters between the two groups. Taken together, BMP4 gene therapy inhibited myeloma tumor growth, but also reduced the amount of trabecular bone in mice. Our data suggest that care should be taken when considering using BMP4 as a therapeutic agent.

cancer biology↗